Anticholinesterase derivatives



UNITED STATES PATENT OFFICE.

ANTICHOLINESTERASE DERIVATIVES Frederick Charles Copp, London, England, as-

signor to Burroughs Wellcome & 00. (U. S. A.)

- Inc.', Tuckahoe, N. Y., a corporation of New .York.

No Drawing. Application October 3, 1952, Serial No. 313,080

Claims priority, application Great Britain October 11, 1951 g 7 Claims. (Cl. 260-5675) 1 2 The present invention relates to new chemical Y is a group which will form an anion in the compounds exhibiting anti-cholinesterase activity final quaternary compound and which may be the and useful in the treatment of myasthenia gravis. same as X or different. The group Y may be con- In the British Journal of Pharmacology and verted to the group X by any convenient double Chemotherapy, volume 4, page 219, 1949, the antidecomposition reaction.

cholinesterase activity of the compound 1:5-bis- The reaction may conveniently be performed in (4 trimethylammoniumphenyl) pentan 3- a solvent such as propanol, ethanol or acetone. one diiodide, (Formula I) is described. The invention will now be described with refer- Hannah-Gordon).ooomom-Q-momm (I) By further research into allied compounds it has ence to the following examples in which all temnow been found that higher anti-cholinesterase peratures are given in degrees centigrade. activity is exhibited by compounds of the general Formula II, in which R is a normal propyl, or allyl Example 1 group (R=CH2.CH2.CH3 or -CH2.CH:'CH2), 1:5 bis(4 dimethylaminophenyl)pentan 3- andX is an anion. one (1 g.) was dissolved in acetone (5 ml.) ,allyl imomnfi-Gcmomccement-@hwnomi If R is an alkyl group containing less or more iodide (2 g.) added and the resulting solution than 3 carbon atoms or is a benzyl group, the heatedunder reflux. A crystalline solid rapidly anti-cholinesterase activity is considerably less separated from the solution. After 30 minutes than that shown by the compounds in which R is the reaction mixture was cooled, the solid filtered an n-propyl or allyl group. and dried in a vacuum desiccator and the result- The compounds of the general series repreing 1:5-bis(4-allyldimethylammonlumphenyl)- sented by Formula II show a marked inhibitory pentan-3-one diiodide crystallized from methanol action on true cholinesterase and very little acas colorless flat needles, melting point 1795-1805 tion on pseudo-cholinesterase. The compounds (with decomposition). Yield 1.7 g. (The melting of the present invention show even more marked point of this and all other compounds described selectivity for true cholinesterase than does the in this specification are much influenced by the known compound (I). The limiting molar conrate of heating.) centration at which they cause a substantial in- Example 2 hibition of cholinesterase activity is approximately /5 to of the lowest molar concentration 1 :5 bis(4 dimethylaminophenyl)pentan 3- at which the compound of Formula I causes a on (1 g.) and allyl iodide (2.0 g.) were reacted similar inhibition of the enzyme. Nevertheless together in boiling ethanol (5 ml.). After 30 the new and the known compounds have substanminutes, the solution was cooled. The separated tially similar toxicities when injected intravenousend, 1 :5-bis (4-allyldimethylammoniumphenyl) 1y into mice. Therefore it is an additional adpentan-B- ne diiodide, was u t and crysta], vantage of the compounds of the present inVeIllized from methanol, and had a melting point of tion that they have a larger margin of safety 179,5 130,5 Yield 14 g. than the known compound.

The nature of the anion X is unimportant, and Example 3 may conveniently be, for example, chloride iodide, 1:5 bis(4 dimethylaminophenyl)pentan 3- bromide or methansulphonoxy. The compounds one (1 g.) and allyl bromide (2 ml.) were reacted are prepared by reacting 1:5-bis(4-dimethy1- together in boiling acetone (5 ml.). After 1 hour, aminophenyl) pentan-3-one (Formula III) with a the semi-solid mixture was cooled and the resultcompound of the RY, ing 1 :5-bis(4-allyldimethylammoniumphenyl) (cushy-Gammondemote-Gwen),

in which R is a normal propyl or allyl radical, and pentan-3-one dibromide collected and crystallized from ethanol, when it formed colorless plates, melting point 198-199".

Example 4 1 :5-bis(4-allyldimethylaminophenyl) pentan-3- one diiodide (1 g.) prepared as in Examples 1 or 2, was added to a suspension of finely-divided silver bromide (3 g.) in water (10 ml.). The mixture was stirred and heated" to boiling for 15 minutes, filtered and the filtrate evaporated under reduced pressure. Acetone was added .to the? 'esidual gum which rapidly crystallized. The acetone was decanted and the residue recrystallized from ethanol to give colorless plates of 1:5-bismallyldimethylammoniumphenyl pentah-S-one dibromide, melting point 198-199.

By use of silver chloride in place of silver bromide there results 1:5-bis(4-allyldimethylammoniumphenyl) pentan 3 one dichloride; it is very deliquescent.

4 crystallized on standing at It was recrystallized from ethanol and formed short, thick needles of 1 :5-bis (4-dimethylpropylammoniumphenyl) pentan-B-onediiodide (1.8 g.) melting point 180.

0 Example 7 1:5 bis(4 dimethylaminophenyl) pentan 3- one (10 g.) and n-propyl bromide (20 ml.) were dissolved tog'ether in n-propanol (50 m1.) and the 10 solution heated to reflux for 2 hours. The bulk of the solvent wasthen removed under reduced pressure and acetone (50 m1.) added to the residue, which then crystallized. The solid was collected, dissolved in ethanol and the solution shaken with charcoal and filtered. The filtrate was concentrated and acetone added, to give crystals of 1:5 bis(4 dimethylpropylammoniumphenyl)- pentan-B-one dibromide, melting point 187-189.

Iclaim:

1. Compounds of the formula:

xmonam-G-omomo osmom-Q-mcnmnx Example 5 1 :5 bis(4 dimethylaminophenyl)pentan 3- one (1v g.) and allyl methane sulphonate (4 g.) were reacted together in boiling acetone. An oil slowly separated. After 4 hours, the mixture was cooled and the supernatant liquid decanted off the product, which was a gum. This product, 1:5 bis 4 allyldimethylammoniumphenyl) pentan-3-one-bis(methane sulphonate) was dissolved=-in water (10-ml.) and excess potassium iodide (55- g.) added. An oil separated which rapidly solidified. This solid was filtered, washed with a little cold water and pressed on a porous plate tossdry. On. repeated crystallization from methanol, it gavepure 1:5-bis(4-allyldimethylammoniumphenyl)pentan-3-one diiodide, melting point 179-180". (Yield 1.0 g.).

Example 6 After 3 hours,

wherein R is selected from the class consisting of propyl and allyl groups, and X is the anion of a therapeutically acceptable acid.

2. A (ii-quaternary salt of the cation 1:5-bis- (4 allyldimethylammoniumphenyl)pentan 3- one in combination with a therapeutically acceptable acid.

3. A di quaternary salt of thecation 1:5-bis(4- dimethylpropylammoniumphenyl)pentan 3-one in combination with a therapeutically acceptable acid.

4. 1:5 bis.(4-allyldimethylammoniumphenyl) pentan-3-one diiodide.

y 5. 1:5 bis(4 dimethylpropylammoniumphenyl) pentan-3-one diiode.

6. 1:5 bis(4-allyldimethylammoniumphenyl) pentan-3-one dibromide.

7. 1:5 bis(4-allyldimethylammoniumphenyl) pentan-3-one dichloride.

References Cited in the file of this patent Burgen, Br. J; Pharmacol and Chemotherapy, vol. 4 (1949,13. 223. 

1. COMPOUNDS OF THE FORMULA: 